Altered Pharmacokinetics of Cimetidine Caused by Down-regulation of Renal Rat Organic Cation Transporter 2 (rOCT2) after Liver Ischemia-Reperfusion Injury
Altered Pharmacokinetics of Cimetidine Caused by Down-regulation of Renal Rat Organic Cation Transporter 2 (rOCT2) after Liver Ischemia-Reperfusion Injury
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DOI：
10.2133/dmpk.dmpk-13-rg-021
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发表时间：
2013-12-25
影响因子：
2.1
通讯作者：
Okuda, Masahiro
中科院分区：
文献类型：
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作者：
Ikemura, Kenji;Nakagawa, Erika;Okuda, Masahiro
肾小管分泌阳离子药物主要由基底外侧有机阳离子转运蛋白 2 (rOCT2/SLC22A2) 和管腔多药和毒素排出 1 (rMATE1/SLC47A1) 主导。关于肝脏缺血再灌注（I/R）损伤后这些肾脏转运蛋白表达的变化知之甚少。在这里，我们检查了阳离子药物西咪替丁的药代动力学、肾脏 rOCT2 和 rMATE1 水平及其在肝脏 I/R 后的调节。大鼠经历 60 分钟的肝脏缺血，然后再灌注 12 小时。再灌注前 5 分钟静脉注射抗氧化剂 Trolox (R)。与假手术大鼠相比，I/R大鼠中西咪替丁的全身和肾小管分泌清除率（78%和55%）以及肾rOCT2和rMATE1水平（67%和61%）分别降低。然而，肝脏I/R后，西咪替丁的肾组织与血浆浓度比下降，但肾组织与尿液清除率却没有下降。此外，Trolox 还可防止肝脏 I/R 后肾脏 rOCT2 水平的降低和西咪替丁的全身清除。这些结果表明，肝脏I/R减少了西咪替丁的肾小管分泌，主要是因为肾脏中rOCT2水平降低，并且氧化应激应该是肝I/R损伤后肾脏rOCT2降低的部分原因。
The renal tubular secretion of cationic drugs is dominated by basolateral organic cation transporter 2 (rOCT2/SLC22A2) and luminal multidrug and toxin extrusion 1 (rMATE1/SLC47A1). Little is known about the variation in the expression of these renal transporters after liver ischemia-reperfusion (I/R) injury. Here, we examined the pharmacokinetics of a cationic drug, cimetidine, and renal rOCT2 and rMATE1 levels as well as their regulation after liver I/R. Rats were subjected to 60 min of liver ischemia followed by 12 h of reperfusion. The antioxidant Trolox (R) was administered intravenously 5 min before reperfusion. The systemic and tubular secretory clearances of cimetidine (78% and 55%) as well as renal rOCT2 and rMATE1 levels (67% and 61%) in I/R rats were decreased compared with those in sham-operated rats, respectively. However, the renal tissue-to-plasma concentration ratio but not the renal tissue-to-urine clearance ratio of cimetidine was decreased after liver I/R. Moreover, Trolox prevented the decreases in renal rOCT2 levels and systemic clearance of cimetidine after liver I/R. These results demonstrate that liver I/R decreases the tubular secretion of cimetidine, mainly because of the decreased rOCT2 level in the kidney, and that oxidative stress should be responsible in part for decreased renal rOCT2 after liver I/R injury.